Malaria remains a disease of devastating proportions in developing countries around the world. It is estimated that 200 million infections occur each year, resulting in at least 2 million deaths, primarily among young children. There is as yet no vaccine for malaria and current drug therapies are inadequate due to the rapid development of resistance of the malarial parasite Plasmodium to the agents that are being used. An attractive new strategy for therapeutic intervention in this disease is to interrupt the complex life cycle of the parasite in its human host. During this dramatic morphologic transformations that define the life cycle of Plasmodium, the parasite must restructure entire organelles and rearrange elements of its cytoskeleton. We hypothesize that the proteasome of the parasite mediates the massive proteolysis that accompanies this remodeling. Inhibitors of the proteasome should therefore prevent this remodeling and lead to death of the parasite. In this application, we present preliminary data supporting this hypothesis and a Phase I research plan that would identify, from among ProScript's proprietary proteasome inhibitors, potent and selective inhibitors of Plasmodium proteasome that can halt the development of Plasmodium falciparum in human blood. These studies lay the foundation for a future Phase II study in which we develop one of these compounds into an orally active agent that is efficacious in mice infected with Plasmodium berghei and non-human primates infected with the human-infective parasite Plasmodium falciparum. PROPOSED COMMERCIAL APPLICATION: The goal of this work is to identify proteasome inhibitors that could be developed into effective drugs that would be marketed to treat malaria.